Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose. It affects 10-20% of the world's population older than 45 years of age and it is achieving epidemic proportions in some populations. NIDDM is a leading cause of morbidity and death and it has an enormous economic impact on society. One study estimates the direct costs of medical care for NIDDM in the United States to be $85.7 billion in 1992. Genetic factors play an important role in the etiology of NIDDM as shown by the almost absolute concordance of diabetes in monozygotic twins, concordance rates higher than 40% in sibs and non-identical twins. It is the main goal of my laboratory to identify the genetic factors that predispose individuals to develop type 2 diabetes and to develop a genetic classification of NIDDM which may allow earlier diagnosis and treatment, risk assessment as well as more specific therapies of type 2 diabetes. To accomplish this goal, human clinical investigation, complemented by molecular genetic and animal studies, is a necessity. Four studies are proposed in this grant application. Emphasis will be placed on two large outpatient studies in which several hundred families with type 2 diabetes will be characterized for genetic studies. The third is an inpatient study which aims to characterize the pancreatic -cell defect in patients with early-onset type 2 diabetes which are unlinked to the MODY1-5 loci. The fourth study is designed to elucidate the molecular mechanisms of central obesity by analyzing and comparing adipocyte gene expression in omental vs. subcutaneous fat.